Modafinil vs Adderall - A Side-By-Side Comparison

Modafinil vs Adderall Summary

So what are the key differences between modafinil vs Adderall?

Adderall is comprised of mixed amphetamine salts. Amphetamines are an old-school drug with a well-characterized mechanism used by both Adolf Hitler and JFK. Amphetamines were repurposed for the treatment of ADHD in the 1990’s, when Adderall was approved by the FDA.

By contrast, modafinil is a relatively new drug with a novel mechanism. Modafinil banishes fatigue without the edginess associated with psychostimulants. Modafinil is safer than amphetamines, but less effective at controlling the core inattentive symptoms of ADHD.

Both drugs are increasingly being used in the workplace and in school to enhance productivity.

ADHD diagnosis rates have increased as the workforce shifts away from blue-collar work toward white-collar desk jobs. A recent article entitled Gin and juice: modafinil tightens up the drinker’s brain at rest describes how modafinil improves the functional connectivity of the default mode network in former alcoholics. The default mode network is just the pattern of neural activity at rest – when your brain isn’t engaged with anything in particular.

It's recent research like the finding that modafinil improves how neurons in the brain talk to one another that has led to the view of modafinil as a nootropic (cognitive enhancer).

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Adderall mimics the fight-or-flight response by promoting catecholamine release. Modafinil has a novel mechanism of action that involves glutamate/GABA, catecholamines, orexin/histamine and gap junctions between neurons

Adderall use is more likely to result in dependence or abuse. Modafinil has negligible abuse potential

Adderall is associated with more adverse effects than modafinil, but is more effective at managing the core symptoms of ADHD

Studies have been mixed, but amphetamines and modafinil may improve cognition in healthy subjects. If these results are confirmed, these drugs would only improve cognition for certain type of tasks. Moreover, Adderall and modafinil do not benefit high-performing individuals.

Modafinil and Adderall are used for different purposes and don’t fall within the same class of medications. In a sense, the modafinil vs amphetamines comparison is like comparing apples to oranges. Provigil (modafinil) is an anti-fatigue agent, whereas amphetamines acts directly on the dopaminergic reward centers to increase executive function.

The worst-case adverse effect for modafinil is the development of Stevens-Johnson syndrome (SJS), which can be lethal if left untreated. Adderall may rarely precipitate psychosis, adversely affects cardiovascular health, may promote strokes and hypertension.

Cognitive Enhancing (Nootropic) Effects of Adderall

A number of studies have directly compared modafinil and classic catecholaminergic psychostimulant agents. This table was originally published by Minzenberg et. al.[^10]

Adderall is a prescription psychostimulant that promotes the release of catecholamines (dopamine, norepinephrine) and to a lesser extent serotonin in the brain.

Individuals with attention-deficit hyperactivity (ADHD) are classically calmed down by Adderall, whereas Adderall is experienced as more stimulating and mood-elevating in healthy subjects.

The subjective effects of Adderall include enhanced motivation, concentration, executive function, goal-oriented behavior and organization. Two studies published this year indicate that Adderall may be a nootropic (neuro-enhancer) even in healthy subjects [^1][^2]. One of these studies [^2] was a meta-analysis conducted with over 1400 participants, and demonstrated modest improvement in cognitive measures in subjects without ADHD:

Forty-eight studies (total of 1,409 participants) were included in the analyses. We found evidence for small but significant stimulant enhancement effects on inhibitory control and short-term episodic memory. Small effects on working memory reached significance, based on one of our two analytical approaches.

Effects on delayed episodic memory were medium in size. However, because the effects on long-term and working memory were qualified by evidence for publication bias, we conclude that the effect of amphetamine and methylphenidate on the examined facets of healthy cognition is probably modest overall. In some situations, a small advantage may be valuable, although it is also possible that healthy users resort to stimulants to enhance their energy and motivation more than their cognition.

Adderall use carries significant risks, however. It's associated with adverse events, such as the precipitation of psychosis. Other side effects including insomnia, dependence, personality changes, hypertension, and Reynaud’s syndrome (impaired circulation to the extremities).

Cognitive Enhancing (Nootropic) Effects of Modafinil

Modafinil has been reported to enhance cognitive performance in schizophrenic patients as an adjunct to antipsychotic medication [^3], in healthy sleep-deprived [^4] and non-deprived subjects alike [^5], and improves executive function in alcohol-dependent patients by modulating the functional connectivity of the default mode network [^6].

Quick aside: the default mode network (DMN) is comprised by the brain structures maximally active at rest, and the functional connectivity of this network is classically disrupted in chronic alcoholism.[^7]

But the degree of improvement is likely related to baseline intelligence. This means that negligible benefits are appreciated by people at the highest end of the IQ bellcurve.

One study [^8], published in Psychopharmacology, concluded the following:

Modafinil significantly enhanced performance on tests of digit span, visual pattern recognition memory, spatial planning and stop-signal reaction time. These performance improvements were complemented by a slowing in latency on three tests: delayed matching to sample, a decision-making task and the spatial planning task. Subjects reported feeling more alert, attentive and energetic on drug. The effects were not clearly dose dependent, except for those seen with the stop-signal paradigm. In contrast to previous findings with methylphenidate, there were no significant effects of drug on spatial memory span, spatial working memory, rapid visual information processing or attentional set-shifting. Additionally, no effects on paired associates learning were identified.

Let's compare modafinil verses Adderall in terms of their nootropic effects. Both drugs clearly enhance cognition in a subset of the population.

Modafinil is most likely to confer cognitive benefits to individuals impaired by sleep deprivation or by a neuropsychiatric disorder associated with cognitive deficits like schizophrenia, depression or bipolar disorder.

Adderall is most likely to improve cognitive function in patients with ADHD or in healthy individuals that have a polymorphism. For example, a genetic variant that affects dopamine metabolism or the sensitivity and density of dopamine receptors.